Impact of hormonal contraceptives on sex differences in fear conditioning and fear extinction in PTSD

Sex differences in the neurobiological mechanisms involved in fear conditioning and extinction have been suggested to contribute to differential vulnerability for the development of posttraumatic stress disorder (PTSD) in women compared with men. Reproductive hormones, such as estradiol, have been shown to facilitate fear conditioning and extinction learning and may explain some of these differences. However, the effect of commonly used hormonal contraceptives on the neurobiological mechanisms of fear conditioning and extinction is poorly understood. A laboratory study was conducted in trauma-exposed men and women with and without full or partial PTSD to examine effects of sex and use of hormonal birth control on fear conditioning, fear extinction learning, and extinction retention. Participants underwent fear conditioning with stimuli that were paired (CS+) or unpaired (CS−) with shock. Extinction learning occurred 72 h later, and extinction retention was tested 1 wk after extinction. Women on hormonal contraceptives (HCs) demonstrated enhanced acquisition of fear conditioning and enhanced extinction of fear as compared with women off hormonal birth control and men. While clinical implications have yet to be determined, these results suggest that hormonal contraceptives may facilitate learning during both fear acquisition and extinction. Understanding the impact of sex and hormones on fear conditioning and extinction processes may lead to new insights into the pathophysiology of PTSD and result in advancements in treatment that may vary by sex.

It is widely recognized that posttraumatic stress disorder (PTSD) is a common consequence of trauma exposure, and women are at particularly high risk, with some but not all studies finding that women develop PTSD at twice the rate of men, despite greater trauma exposure in men (Breslau et al. 1998; Tanielian et al. 2008). Although some have suggested that greater exposure to interpersonal violence may contribute to higher rates of PTSD in women, other evidence implicates sex differences in the neurobiological mechanisms that are involved in fear conditioning and extinction. Enhanced fear conditioning and diminished extinction of conditioned fear have been associated with higher levels of endogenous estrogen in women, as well as the development and maintenance of PTSD in both sexes (Orr et al. 2000; Milad et al. 2009b; Glover et al. 2012). Furthermore, as one of the most empirically supported treatments for PTSD is prolonged exposure therapy, which is largely based on fear extinction principles and the success of extinction learning (Rothbaum and Davis 2003), a clear understanding of the individual factors impacting fear conditioning and extinction is critical.Although some of the studies examining sex differences in fear conditioning are inconsistent (Guimaraes et al. 1991; Zorawski et al. 2005; Milad et al. 2006), an increasing body of evidence from rodent and human studies supports the existence of sex differences in fear extinction learning and recall (Maren et al. 1994; Pryce et al. 1999; Milad et al. 2009a; Merz et al. 2013). One possible explanation for the lack of consistent findings in the fear conditioning literature may be related to potential floor effects associated with subclinical impairment of nonclinical samples, as most laboratory studies examining sex differences were conducted in healthy humans. Another explanation that is gaining substantial support is the impact of hormones that differ between the sexes, among individuals, and even within individuals across time (Quirk and Mueller 2008; Lebron-Milad and Milad 2012; Arevalo et al. 2015; Hwang et al. 2015; Herrera et al. 2017; Maeng et al. 2017; Antov and Stockhorst 2018).The available literature indicates that estradiol, the primary estrogen in women during the childbearing years, is also present at overall lower concentrations in males and plays a large role in the fear conditioning and extinction differences observed between men and women (Gupta et al. 2001; Jasnow et al. 2006; Chang et al. 2009; Milad et al. 2009a, 2010; Zeidan et al. 2011; Maddox et al. 2018; Matsumoto et al. 2018; Carvalho et al. 2021). In both sexes, estradiol plays a variety of important functions in the brain, including the regulation of oxidative stress, inflammation, and gene expression, as well as in cognitive functions such as learning and memory (Hammoud et al. 2020). Estrogen receptors are found throughout brain regions that are important for fear conditioning and extinction processes (e.g., the amygdala, ventromedial prefrontal cortex, and hippocampus), likely via enhancements to learning and memory (Milad et al. 2008; Quirk and Mueller 2008; Lebron-Milad and Milad 2012). In women, as peripheral levels of estradiol vary over the course of the menstrual cycle, so do levels of estradiol in the brain (Arevalo et al. 2015). Estradiol has been shown to enhance memory consolidation across stages of fear conditioning, extinction, and retention (Lebron-Milad and Milad 2012). Most relevant to learning in PTSD, women with high levels of estradiol demonstrate enhanced memory formation in the presence of stress exposure (Herrera et al. 2017; Antov and Stockhorst 2018). In animal and human models, higher estradiol levels appear to facilitate acquisition of fear conditioning and extinction (Maeng et al. 2017). For example, women with high endogenous estradiol levels have enhanced responses in fear circuitry during fear conditioning, extinction, and recall as compared with men (Hwang et al. 2015). When phase of menstrual cycle has been taken into account, differences have been observed in conditioned fear responses and severity of PTSD symptoms. Specifically, when women are in the midluteal phase of the menstrual cycle (higher endogenous estradiol), they demonstrate a stronger positive relationship between SCR during fear conditioning and PTSD symptoms than women in the early follicular phase of menstruation (lower endogenous estradiol) (Carpenter et al. 2022). In the complimentary literature on the startle response, low-estradiol women demonstrated reduced discrimination between CS+ and CS− during fear conditioning and reduced inhibition of fear-potentiated startle during extinction and extinction recall, indicating less successful learning than their high-estradiol counterparts (Glover et al. 2012, 2013; Armbruster et al. 2018). This literature suggests that higher levels of estradiol relate to enhanced acquisition of associations between an unconditioned stimulus (UCS) and a conditioned stimulus (CS) during fear conditioning and enhanced extinction of this association during the extinction phase due to greater memory consolidation.A variety of factors can account for hormone differences in women, including menstrual phase, age, and use of hormonal birth control. Approximately 11%–20% of women aged 20–39 yr use oral contraceptives (OCs) (Daniels and Abma 2020). Commonly used OCs directly affect estradiol levels and hormonal fluctuation associated with the menstrual cycle. However, hormonal contraceptives (HCs) have received little attention in the fear conditioning literature. At the time of writing, we were unable to locate studies examining the impact of other HCs on fear conditioning circuitry, although these forms of birth control are increasingly popular among women, and evidence suggests that a variety of HCs has impacts on brain structure, function, and cognitive processes (Brønnick et al. 2020). Literature suggests that estradiol levels in women on HCs are typically low, similar to those of women in the early follicular phase of menstruation (Brynhildsen 2014). Although Hwang et al. (2015) did not demonstrate an effect of HCs on fear conditioning, many HCs contain ethinyl estradiol, which is synthetic estrogen that binds to estrogen receptors at high levels. Further research is needed to determine whether synthetic estrogen present in HCs impacts fear conditioning and fear extinction and contributes to associated sex differences, particularly in a highly sensitized population such as those with PTSD. In the current study, differences in fear conditioning, extinction, and retention were examined in women on hormonal birth control and in the early follicular phase of the menstrual cycle as compared with men to determine whether the synthetic hormones present in HCs confer any enhancement to these processes over and above women off of birth control with theoretically low levels of endogenous estradiol.Fear conditioning is measured by assessing the differential SCR to a conditioned stimulus (CS+) paired with an unconditioned stimulus (shock; UCS) and a stimulus unpaired with a shock (CS−). Greater acquisition of fear conditioning is evidenced by greater SCR response to the CS+ when compared with the CS−. Fear extinction refers to repeated exposure to the CS in the absence of the US, which results in diminishing reactivity to previously conditioned stimuli due to an inhibitory neural link that is formed (Myers and Davis 2007). Extinction is therefore operationalized by reduced discrimination of responding to the CS+ and CS− over time, and its retention is evidenced by a maintenance of low differential SCR in response to presentation of CS+ and CS− cues at follow-up.In previous work, our group examined sex differences in skin conductance responses to a fear conditioning paradigm in men and women with PTSD (Inslicht et al. 2013). In that sample, women were premenopausal and underwent conditioning during the follicular phase of the menstrual cycle. We found that women had greater differential fear acquisition compared with men. Other work has indicated that the effects of endogenous gonadal hormones on fear extinction are moderated by PTSD diagnosis, such that women with PTSD demonstrated impaired fear extinction during the midluteal phase of menstruation but not during the early follicular phase (Pineles et al. 2016b). The current study examines the effect of sex, HC use, and PTSD severity on fear conditioning, fear extinction, and extinction retention in medically healthy trauma-exposed premenopausal women on or off HCs and age-matched men across a range of PTSD symptom severity. We used a validated laboratory conditioning paradigm (Inslicht et al. 2021) that occurred over several days in which fear acquisition was separated from extinction by 72 h to avoid influencing consolidation of fear conditioning, and extinction retention was evaluated 1 wk after the fear extinction session to provide a test of durability of extinction over time.Given evidence for impaired fear extinction in PTSD, we hypothesized that participants high in PTSD (men and women combined) would have decreased fear extinction learning and extinction retention compared with those with low PTSD symptom scores. As estradiol appears to enhance learning during stress in women, we predicted that women on HCs would demonstrate higher differential SCR during acquisition and lower differential SCR during extinction and extinction retention than naturally cycling women in the early follicular phase of menstruation and men. Finally, we predicted a PTSD × sex interaction effect for extinction learning and retention; women on HCs with high levels of current PTSD would have enhanced acquisition but decreased extinction learning and retention compared with women with low levels of current PTSD and men.     

Chronic stress and sex differences on the recall of fear conditioning and extinction

Chronic stress effects and sex differences were examined on conditioned fear extinction. Male and female Sprague–Dawley rats were chronically stressed by restraint (6 h/d/21 d), conditioned to tone and footshock, followed by extinction after 1 h and 24 h delays. Chronic stress impaired the recall of fear extinction in males, as evidenced by high freezing to tone after the 24 h delay despite exposure to the previous 1 h delay extinction trials, and this effect was not due to ceiling effects from overtraining during conditioning. In contrast, chronic stress attenuated the recall of fear conditioning acquisition in females, regardless of exposure to the 1 h extinction exposure. Since freezing to tone was reinstated following unsignalled footshocks, the deficit in the stressed rats reflected impaired recall rather than impaired consolidation. Sex differences in fear conditioning and extinction were observed in nonstressed controls as well, with control females resisting extinction to tone. Analysis of contextual freezing showed that all groups (control, stress, male, female) increased freezing immediately after the first tone extinction trial, demonstrating contextual discrimination. These findings show that chronic stress and sex interact to influence fear conditioning, with chronic stress impairing the recall of delayed fear extinction in males to implicate the medial prefrontal cortex, disrupting the recall of the fear conditioning acquisition in females to implicate the amygdala, and nonstressed controls exhibiting sex differences in fear conditioning and extinction, which may involve the amygdala and/or corticosterone levels.     

条件性恐惧泛化的性别差异

恐惧的过度泛化是焦虑障碍的核心症状之一, 表现为患者对与原危险刺激极不相似的中性刺激也有着较高强度的恐惧反应。临床上, 女性比男性更有可能患焦虑障碍, 因而对恐惧泛化进行性别差异研究可以为解释女性有着更高焦虑障碍发病率提供新的角度, 同时为临床治疗提供参考。本研究采用辨别性条件恐惧范式, 以主观预期值和皮电反应值作为测量指标, 从行为和生理两个层面对条件性恐惧泛化程度和恐惧泛化消退的性别差异进行研究。结果发现, 在恐惧泛化程度上, 未出现显著性别差异。在恐惧泛化消退上, 在主观预期值和皮电反应值两个层面均有着显著性别差异, 具体表现为相较于男性, 女性恐惧泛化的消退更慢, 持续时间更长。研究结果表明, 女性焦虑障碍高发病率的潜在影响因素之一可能在于女性对于恐惧泛化刺激的难以消除。     

Relative influence of sex composition on job desirability

The purpose of this study was to examine the relative influence which the sex composition of a job exerts on its perceived desirability. The influence of job sex composition was studied in relation to three other factors: security, suitability of type of work, and company recognition. Ninety-five college students rated 108 job profiles on desirability based on various combinations of the four factors studied. The results indicated that sex composition exerted the least influence on job desirability while security and suitability of type of work exerted the greatest influence. It is suggested that past research focusing on the sex composition of a job as a determinant of its desirability has produced findings which are primarily a function of the research method utilized.     

Social evaluation fear in childhood and adolescence: Normative developmental course and continuity of individual differences

Using cross‐sectional (N =910) and longitudinal (N =261) data from Gullone and King's (1993, 1997 ) studies of normal fear in children and adolescents aged 7 to 18 years, the normative developmental pattern of social evaluation fear and the continuity of individual differences were investigated. Participants' responses were analysed according to two subscales (Social Evaluation and Punishment) within the Failure and Criticism scale of the Fear Survey Schedule. The findings indicated that: (a) social evaluation fear increased between childhood and adolescence, while punishment fear decreased, (b) individual differences in social evaluation fear displayed only modest continuity over the 3‐year follow‐up period, (c) continuity of social evaluation fear increased with increased age and (d) discontinuity was particularly salient for relatively high fear levels.     

Social desirability and Wiggin's MMPI content scales.

Using the Minnesota Multiphasic Personality Inventory (MMPI) item pool, Wiggins (1966) developed 13 scales, each with a homogeneous content. The 13 scales, along with marker scales for the 1st 3 MMPI factors, Edward's social desirability (SD), Welsh's repression (R), and Wiggins's social desirability (Sd) respectively were scored in the MMPI. The same scales were scored in an Experimental Multiphasic Personality Inventory (EMPI). A principal-components analysis of the 16 scales when scored in the MMPI resulted in 4 factors. A principal-components analysis of these same scales when scored in the MMPI and when scored in the EMPI were found to be highly congruent. The SD, R, and Sd scales proved to be excellent markers for the 1st 3 factors of the MMPI and also for the 1st 3 factors of the EMPI. Results provide further evidence that the 1st MMPI factor is a social desirability factor rather than a content factor.     

Social desirability, approval and public good contribution

Behaviour in public good experiments is usually attributed partly to rational self-interest and partly to social norms and preferences. This paper examines if sensitivity to social desirability affects public good contribution and in what way. A pre-experimental measure of social desirability (SDS17) was used to match partners in a two-person public good game. Half the participants received experimenter approval based upon their investment. Contrary to predictions, the highest public good investment was by low social desirability participants in the approval condition. Social desirability was not positively related to pro-social behaviour. We consider its relation to experimental and social conformity.     

Social desirability of subtle and blatant prejudice scales

The present paper analyzes the relation between the measurement of subtle and blatant prejudice proposed by Pettigrew and Meertens in 1995 and the tendency to give socially desirable responses. It also tests whether items that measure subtle prejudice are judged as more socially desirable than those that measure blatant prejudice. Data were obtained from two groups, one of 497 Italian high school students and one of 77 university students. In the first case, the analysis concerns the relation between the prejudice scores and scores on a shortened form of Marlowe and Crowne's Social Desirability Scale. In the second case, we analyzed the social desirability judgments expressed on single items of the Petrigrew and Meertens scales. Analyses indicate that (1) neither Subtle nor Blatant Prejudice scores correlate with the tendency to give socially desirable responses and (2) when the items of the two prejudice scales are placed in order on the social desirability continuum, with very few exceptions the Blatant Prejudice items are situated at the not socially acceptable pole and Subtle Prejudice items at the socially acceptable pole.